In situ formation of polymeric material

ABSTRACT

A pharmaceutically acceptable bio-adhesive coating, film or gel is formed in situ at a body surface by the reaction of (i) an anionic polymer or tripolyphosphate and (ii) a cationic polymer in the presence of water. The two components are supplied either as separate aqueous solutions or in a single non-aqueous formulation, which can be a liquid suspension tablet, capsule or powder.

This invention relates to polymeric material, for example, coatings,films and gels, especially pharmaceutically acceptable bioadhesivecoatings, films and gels and more specifically to improved methods forproducing such coatings, films and gels.

Many polymers are known to be bioadhesive (i.e. able to adhere tobiological surfaces, e.g. mucus, the skin, mucosal surfaces, epitheliumetc.) and the value of this property is well recognised. For example,bioadhesives may be used to adhere active agents to specific sites inthe body for local drug administration, or to coat particular parts ofthe body. However, when bioadhesives are applied to such surfaces inaqueous solution they may be easily washed off or mechanically removed,because the strength of adhesion of each individual bioadhesive moleculeto the surface is not very high. This may lead to further problems ifthe bioadhesive materials contain active agents intended for use at oneparticular site, but which are washed away to other sites.

Thus to improve the retention of bioadhesives at a surface they may beformed into films. Such films may be formed either by chemicalcrosslinking or by physical interaction of the bioadhesive molecules asthey come out of solution. However, all of the known methods of filmformation have drawbacks with regard to their use at biologicalsurfaces. For example, if bioadhesive films are formed before beingapplied to a surface (e.g. by weaving polymer strands or by slowevaporation of aqueous solutions of the polymers) they will be awkwardto apply to relatively inaccessible parts of the body (e.g. the back ofthe throat or the underside of the tongue); furthermore, for a number ofbiopolymers, much of the bioadhesive character of the films may be lostif they become too dry.

Alternatively, current methods for forming bioadhesive films directly ona surface require the use of volatile solvents, which quickly evaporateto leave a film, but which are not suitable for use on sensitive areasof a body (e.g. open wounds, mucosal surfaces, etc.).

A need exists for coatings, gels and/or films, especially bioadhesivecoatings, gels and films, capable of being formed directly on surfaceswhich avoids the use of volatile solvents.

A further need exists for a formulation which is capable of forming abioadhesive coating, film or gel in situ and which may be provided tothe consumer in stable form in a single dosage form containing bothcomponents.

According to the invention there is provided a pharmaceuticallyacceptable polymeric material formed in situ at a body surface, whereinthe material is formed by the reaction of:

i) an anionic polymer or tripolyphosphate (component a); and

ii) a cationic polymer (component b) in the presence of water.

Further according to the invention there is provided a process for thepreparation of a pharmaceutically acceptable polymeric material in situat a body surface by applying

i) an anionic polymer or tripolyphosphate (component a) and;

ii) a cationic polymer (component b)

to the body surface wherein component a) is capable of reacting withcomponent b) to form the polymeric material.

Preferably the polymeric material is a bioadhesive coating, film or gel.

Preferably, the polymers are applied sequentially and the first appliedpolymer is a bioadhesive polymer.

Preferably component a) has one or more acid (proton donor) groups, forexample —COOH and/or —SO₃H.

Preferably component b) has one or more basic (proton acceptor) groups,for example —NH₂ and/or NHCH₃.

Component a) may be selected from any anionic polymers that arewater-soluble or dispersible and that will form a coating, gel or filmin the presence of component b). Preferred anionic polymers includewater-soluble salts of hyaluronic acid, water-soluble salts of alginicacids (e.g. sodium alginate, potassium alginate), water-soluble ordispersible salts of polyacrylic acids (e.g. sodium carbomers), xanthangum, acacia, pectins, sterculia, carrageenan salts, polylactic acid andwater-soluble cellulose derivatives (e.g.sodium carboxymethylcellulose). Most preferred anionic polymers for use in the presentinvention are water soluble or dispersible carbomer salts, water-solublesalts of alginic acids and water-soluble salts of cellulose derivatives.

Mixtures of anionic polymers may be used, as long as they do notthemselves crosslink to form films until component b) is added to them.

The concentration of component a) in the the bioadhesive coating, gelsor films of the invention will depend upon a number of factors (e.g. thestrength of the film, gel or coating to be produced, the solubility ofthe polymers, the required viscosity of the solution etc.). Generallythe concentration will preferably be selected from the range 0.1 to 75%weight to volume (w/v), more preferably 0.5 to 25% w/v based on thecomposition as a whole.

Component b) may be selected from any cationic polymers that arewater-soluble or dispersible and that will form a coating, film or gelin the presence of component a). Preferred cationic polymers includewater-soluble chitosan salts (e.g. chitosan chloride, chitosan acetate),polylysine, chondroitin salts, diethylaminoethyl dextran and keratin.

Mixtures of component b) may be used to form the bioadhesive films ofthe invention, as long as they do not interact to form a film themselvesuntil they have been added component a).

The total amount of component b) in the bioadhesive coatings, films orgels of the invention will depend upon a number of factors including theamount of component a) used, the strength of film required, theeffectiveness of component b), etc. Generally the concentration will beselected from 0.1 to 75% w/v, more preferably 0.5 to 25% w/v of thecomposition as a whole.

The preferred amount may be easily determined by simple experimentation,however the total weight ratio of component a) to component b) willgenerally be from 1:10 to 10:1, more preferably 1:2 to 2:1.

The balance of the coating, film or gel may be water, any otherpharmaceutically effective carriers, fillers and/or excipients.

Where component a) is a water-soluble alginate salt, component b) ispreferably selected from water-soluble chitosan salts; diethylaminoethyldextran and chondroitin sulphate; most preferably a water-solublechitosan salt.

Where component a) is a water-soluble or dispersible carbomer salt,component b) is preferably selected from water-soluble chitosan salts;diethylaminoethyl dextran and chondroitin sulphate; most preferably awater-soluble chitosan salt.

Where component a) is sodium carboxymethyl cellulose, component b) ispreferably a water-soluble chitosan salt.

The bioadhesive coatings, films or gels of the invention may optionallyfurther comprise one or more pharmaceutically active agents, for eitherlocal or systematic delivery depending upon the site of application ofthe coating, film or gel.

Suitable active agents for use in such coatings, films or gels of theinvention include analgesics, anti-inflammatory agents and antipyretics(e.g. acetaminophen, ibuprofen, naproxen, diclofenac, ketoprofen,choline salicylate, benzydamine, buprenorphine, hydrocortisone,betamethasone); decongestants (e.g. pseudoephedrine, phenylephrine,oxymetazoline, xylometazoline); mineral salts (e.g. zinc gluconate, zincacetate); cough suppressants (e.g. dextromethorphan, codeine,pholcodine); expectorants (e.g. guaiphenesin, n-acetylcysteine,bromhexine); antiseptics (e.g. triclosan, chloroxylenol, cetylpyridiniumchloride, benzalkonium chloride, amylmetacresol, hexylresorcinol,dichlorobenzyl alcohol, benzyl alcohol, dequalinium chloride, silversulphadiazine); cardiovascular agents (e.g. glyceryl trinitrate); localanaesthetics (e.g. lignocaine, benzocaine); cytoprotectants (e.g.carbenoxolone, sucralfate, bismuth subsalicylate); antiulcer agents(e.g. calcium carbonate, sodium bicarbonate, magnesium trisilicate,magaldrate, cimetidine, ranitidine, nizatidine, famotidine, omeprazole,pantoprazole); antihistamines (e.g. loratidine, terfenadine,diphenhydramine, chlorphenhydramine, triprolidine, acrivastine);antinausea agents (e.g. prochlorperazine, sumatriptan), bowel regulatoryagents (e.g. diphenoxylate, loperamide, sennosides); antifungal agents(e.g. clotrimazole); antibiotics (e.g. fusafungine, tyrothricin) andantipsoriasis agents (e.g. dithranol, calcipotriol).

Mixtures of the active agents may be included in the coatings, films orgels of the invention where appropriate.

The active agents may be contained in either of components a) and b)before they are applied to the body surface, but most preferably theyare contained in component a).

The concentrations of the active agents will depend upon their standarddosages and whether they are for local or systemic release etc.Generally the suitable concentrations will be readily apparent to oneskilled in the art of formulation (normally a concentration range of0.001 to 10% w/v).

Components a) and b) may optionally contain other suitable excipientsdepending upon the proposed site of application. Examples of suitableexcipients include colours, pH adjusters, flavours, sweeteners,preservatives, suspending agents or plasticisers. The concentrations ofsuch excipients will be readily apparent to one skilled in the art offormulation (although they will normally be used in a concentrationrange of 0.001 to 10% w/v).

In a first aspect of the present invention components a) and b) arepresent in aqueous solution.

For the purpose of this invention aqueous solutions of components a) orb) also include aqueous dispersions of said materials.

As hereinbefore described, the aqueous solution of component b) may beapplied sequentially in any order or simultaneously with the aqueoussolution of component a) but more preferably, the aqueous solution ofcomponent b) is applied after the aqueous solution of component a).

The amount of time between the application of the two aqueous solutionsmay vary depending upon the site of application. For example, wherecomponent a) applied first is a biopolymer for use in the throat, thetwo aqueous solutions should be applied within about 10 seconds of eachother. In contrast, on a relatively dry, stable surface such as the armthe aqueous solution which is to be applied second may be applied at anytime within 5 minutes of the application of the solution appliedinitially.

It will be clear that the aqueous solution of component a) and theaqueous solution of component b) must be kept apart until they arecombined as they are applied to the body surface.

The aqueous solutions of component a) and component b) may be applied toa surface by any suitable means, depending upon the nature andaccessibility of the surface. For example, where the surface is arelatively large area that may be suitably positioned (e.g. the back ofa hand, etc.) the solutions may be poured on. The solutions may also beapplied by use of a dropper (e.g. an eye dropper); or they may bepainted on by use of a brush, although care must be taken not to dip thesame brush into the component a) solution and then the component b)solution. Alternatively, the solutions may be dispersed from adouble-chambered tube, or a double-barrelled syringe. Where the film isintended to be formed in the oesophagus, the aqueous solutions may beapplied by being drunk sequentially.

More preferably, the aqueous solutions of component a) and component b)may be sprayed onto the surface.

Any conventional spraying devices may be used for spraying theindividual solutions, for example aerosol sprays, pump sprays or triggersprays. Most preferably, the spray device will be a pump spray or atrigger spray.

Optionally, the two aqueous solutions may be applied by different means,for example the aqueous solution containing component a) may be paintedon and the aqueous solution containing component b) may be sprayed on.

When an aqueous solution of component a) is applied to a surface and anaqueous solution of component b) is applied shortly thereafter(according to a preferred embodiment of this aspect of the invention)only that portion of component a) which comes into contact withcomponent b) will react to form a film. Thus a proportion of componenta) (especially that in closest proximity to the surface) may not simplyform a film but may be coated by the film formed above it. The film inthis case is effectively a coating which can thus encapsulate theunreacted component a) and help to prevent it being removed. Thus thefilm will coat a reservoir of substantially unreacted component a) inthis case. This effect will be most pronounced when the two aqueoussolutions are sprayed onto the surface, because the droplets so formedwill have the most suitable shape to maximise the encapsulation effect.

In a most preferred embodiment of this aspect of the invention there isprovided a process for the preparation of a pharmaceutically acceptablepolymeric in situ at a body surface, the polymeric material coating areservoir of substantially unreacted component a) and holding it inclose proximity to the body surface, comprising the steps of applying anaqueous solution of component a) onto the body surface and subsequentlyapplying an aqueous solution of component b) onto the same surface. Themethod of application is preferably spraying.

Preferably the polymeric material is a bioadhesive coating, film or gel.

In this embodiment, component a) is preferably a bioadhesive polymer,most preferably a water-soluble alginate salt and component b) is mostpreferably a water-soluble chitosan salt. Optionally, the aqueoussolution of component a) also comprises an active agent so that areservoir containing some of the active ingredient may be formed inclose proximity to the surface.

Further according to this first aspect of the present invention, thereis provided the use of:

i) an anionic polymer or tripolyphosphate (component a); and

ii) a cationic polymer (component b)

(and optionally one or more active agents) for the preparation ofaqueous solutions for application to a body surface to form apharmaceutically acceptable polymeric material thereon wherein componenta) is capable of reacting with component b) to form the material.

Preferably the polymeric material is a bioadhesive coating, film or gel.

Preferably the coating includes a reservoir of substantially unreactedcomponent a).

Optionally, the reservoir of unreacted component a) further comprisesone or more active agents such as those exemplified above.

Still further according to this first aspect of the present inventionthere is provided a pharmaceutical pack comprising:

i) an aqueous solution of an anionic polymer or tripolyphosphate(component a); and

ii) an aqueous solution of a cationic polymer (component b)

wherein component a) is capable of reacting with component b) to form apharmaceutically acceptable polymeric material in situ at a body surfaceand the pack is suitable for applying the two solutions to the bodysurface such that the polymeric material is formed at that surface.

Preferably the polymeric material is a bioadhesive coating, film or gel.

The pharmaceutical pack may comprise two discrete containers, one foreach aqueous solution; but preferably the pack will comprise twocontainers which are joined together; or, most preferably, thepharmaceutical pack will comprise a single container having separatecompartments for each aqueous solution.

Where the pharmaceutical pack is a single container it may have separatedispensing means for each solution. For example, there may be spraydispensing means fitted at each end of the container (or next to eachother) to provide sequential spraying of the two aqueous solutions.

Alternatively, in a preferred embodiment, the pharmaceutical packcomprises a single dispensing means which is most preferably aspray-dispensing means. The dispensing means may be adjusted to eitherdispense both aqueous solutions simultaneously, or, more preferably, todispense them sequentially, either by single or multiple activations ofthe dispensing means.

Still further according to this first aspect of the invention, there isprovided the use of a process as described above in therapy, and inparticular for the treatment of diseases of the throat and mouth.

Still further according to this first aspect of the invention, there isprovided the use of a process as described above for the preparation ofa medicament for the treatment of disorders of the upper GI tract.

In a second aspect to the present invention, there is provided anon-aqueous formulation for forming a pharmaceutically acceptablepolymeric material in situ at a body surface, the formulation including

i) an anionic polymer or tripolyphosphate (component a);

ii) a cationic polymer (component b); and

iii) optionally a pharmaceutically acceptable inert filler or carrier

wherein component a) is capable of reacting with component b) to formthe polymeric material in situ following application to or ingestion bya mammal.

Preferably the polymeric material is a bioadhesive coating, film or gel.

The formulation may be liquid or solid.

The pharmaceutically acceptable inert filler or carrier of the inventionmay include a glycol, for example propylene glycol, a medium chaintriglyceride oil, for example, Miglyol (RTM) (Huls Chemicals), aglyceride, for example Transcutol (RTM) (Gattefosse) and/or mannitol.

The formulation of this aspect of the present invention may optionallyinclude one or more active agents, for either local or systemic deliverydepending upon the site of application of the film. In the case ofdelivery to the mouth, for example, active agents may be included toprovide a local effect such as an analgesic or antiseptic action and/orto provide a systemic effect (for example, an anti-histamine or ananti-nausea agent).

Suitable active agents for use in such films or gels of the inventionare as described above.

Mixtures of active agents may be included in the formulation of theinvention, where appropriate.

In addition, the formulations of the present invention may optionallycontain other suitable excipients depending upon the proposed siteand/or mode of application. Examples of suitable excipients are asdescribed above with the inclusion of granulating agents such aspolyvinyl pyrrolidone, and/or magnesium stearate.

Preferably, the mammal is a human although it will be appreciated thatthe present invention can have application in animals.

The present invention thus provides formulations which can be used forpreparing pharmaceutically acceptable bioadhesive coatings, gels andfilms in situ. Unexpectedly, some of the films formed by this processalso have improved properties such as strength and adhesion as a resultof their targeted delivery.

In one embodiment of this second aspect to the present invention, theformulation is presented as a non-aqueous liquid formulation in whichboth component a) and component b) are dispersed or suspended.

Such a formulation may be taken orally by drinking or pouring, or byspraying.

Alternatively, in another embodiment of this second aspect to thepresent invention, the formulation may be in the form of a dry powderwhich contains components a) and b) (and optionally c)) as an intimatemixture. The powder is suitable for delivery to the mouth or throat viaan inhaler. The powder granules, which are of a size of more than 10μm,provide a coating in the mouth or on the throat by absorbing water sothat component a) and component b) may react to form a bioadhesive film.

Equally, in another embodiment of this second aspect the formulation maybe presented in the form of a tablet or lozenge containing bothcomponents necessary to form a bioadhesive film. The tablet or lozengemay be bi-layered, in which case, component a) may be present in onehalf and component b) may be present in the other half. Alternatively,these components could be presented as an intimate mixture.

On ingestion of the tablet, salivation allows release and dissolution ofcomponent a) and component b) so that reaction occurs between them toform a bioadhesive film or a gelatinous mass.

Another embodiment of this second aspect to the present inventionrelates to a formulation which employs a controlled-release capsulecontaining both component a) and component b) within a hard or softcapsule. The capsule is made from gelatin or a suitable equivalent andopens in the stomach to allow reaction of components a) and b) to form abioadhesive film or a gelatinous mass.

The novel formulations of the present invention are all one-componentnon-aqueous systems containing both component a) and component b). Insitu, water which is present at (or which may be provided at) thedelivery site is absorbed by the formulation, thereby enabling componenta) and component b) to react to form a bioadhesive film or a gel.

It will be appreciated by those skilled in the art that component a) andb) will not crosslink to form a bioadhesive coating, film or gel unlessin an aqueous environment. Significant advantages accrue from keepingcomponents a) and b) in a non-aqueous (and therefore non-crosslinking)environment, particularly insofar as the two components may be storedtogether without reacting therefore allowing simultaneous (and thereforequicker) application to a location in a single dosage form.

Components a) and b) may be applied to the surface by any suitablemeans, depending upon the nature and accessibility of the surface and onthe nature of formulation which is appropriate for delivery to thesurface. For example, where the surface is a relatively large area thatmay be suitably positioned (e.g. an external surface such as the back ofa hand, etc.) a liquid formulation may be poured on, or may be appliedby use of a dropper (e.g. an eye dropper), or may be painted on by useof a brush, or may be dispersed from a syringe. Where the film isintended to be formed in the oesophagus, the film could be produced bydrinking a liquid formulation or by the ingestion of a tablet or capsuleformulation. When the film is to be formed on the back of the throat orin the nasal cavity, the dry powder formulation may be the mostappropriate to ensure accurate delivery and film formation.

Any conventional spraying devices may be used for spraying the liquidformulation, for example aerosol sprays, pump sprays or trigger sprays.

Most preferably the spray device will be a pump spray or a triggerspray.

Further according to this second aspect of the present invention, thereis provided the use of the above formulation in therapy, and inparticular for the treatment of diseases of the throat and mouth.

Further according to this aspect of the present invention, there is alsoprovided the use of the above formulation for the preparation of amedicament for the treatment of disorders of the upper GI tract.

The bioadhesive coatings, films or gels according to the invention inthis case may act as a barrier to prevent further damage/contaminationto wounded areas of skin (e.g. wounds, or sites of eczema etc.), tosoothe sore areas of the body (e.g. sore throats etc.); or as systemicdrug delivery films (e.g. transdermal films on intact skin, sublingualdelivery films on the underside of the tongue etc.). Such coatings,films or gels are particularly useful for local delivery of activeagents, as they prevent the active agents from being washed away fromthe site of application, i.e. they minimise the effect of the activeagent on the surrounding tissue (e.g. a topical anaesthetic in thethroat).

The bioadhesive coatings, films or gels of the invention may be formedupon any surface of the mammalian body as required. Suitable surfacesinclude any region of the skin (for example to cover a wound or act as adrug delivery patch), the back of the throat or the oesophagus (e.g. toprovide mechanical protection/soothing, or to deliver active agentslocally or systematically); the underside of the tongue (as a sublingualdosage form the systemic delivery) or in the nasal cavity, vagina orrectum (as local drug delivery forms).

The invention will now be illustrated by the following Examples.

EXAMPLE 1

A. Anionic Solution Sodium alginate (LFR 5/60, 2 g Pronova biopolymer)Methyl paraben (preservative) 0.1 g Flavours, sweeteners, colours q.s.Purified water to 100 ml B. Cationic Solution Chitosan chloride (SeacureCL 211, 0.4 g Pronova Biopolymer) Methyl paraben (preservative) 0.1 gFlavours, sweeteners, colours q.s. Purified water to 100 ml

Solution A

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Create a vortex in the solution and disperse the chitosanhydrochloride. Stir until dissolved.

Solution B

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Create a vortex in the solution and disperse the sodium alginate.Stir until dissolved.

Between 0.2 and 1 ml of each solution may be sprayed simultaneously ontothe back of the throat to form a soothing protective film. This film isof particular benefit to those suffering from a sore throat.

EXAMPLE 2

As Example 1 but the Anionic Solution (A) contains 5% w/v sodiumalginate and the Cationic Solution (B) contains 2% w/v chitosanhydrochloride

EXAMPLE 3

As Example 1 but the Anionic Solution (A) also contains 0.66% w/vlignocaine hydrochloride.

A soothing protective film is formed when 0.5 ml of Solution Aimmediately followed by 0.5 ml of Solution B are sprayed onto the backof the throat. The resulting film also delivers a dose of 3.3 mg oflignocaine hydrochloride providing a local anaesthetic effect.

EXAMPLE 4

A. Anionic Solution As Example 1. B. Cationic Solution Chitosan chloride(Seacure CL 211, 0.4 g Pronova biopolymer) Methyl paraben 0.1 gBenzocaine 0.2 g Amylmetacresol 0.16 g Dichlorobenzyl alcohol 0.24 gFlavours, sweeteners, colours q.s. Purified water to 100 ml

Solution B

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Add the benzocaine, amylmetacresol and dichlorobenzyl alcohol. Stiruntil dispersed.

3. Create a vortex in the solution and disperse the chitosan chloride.Stir until dissolved.

Spray 0.5 ml of Solution B onto the throat immediately followed by 0.5ml of Solution A. A soothing protective film having local antibacterialand local anaesthetic properties is formed at the back of the throat.

EXAMPLE 5

As Example 1 but Solution A also comprises 3 g dextromethorphanhydrobromide and 200 mg of menthol BP.

When 0.5 ml of both Solutions A and B are sprayed onto the back of thethroat of a patient suffering from a cough a demulcent film is producedproviding a local soothing action (due to the menthol) and a systemiccough suppressant effect (due to the dextromethorphan hydrobromide).

EXAMPLE 6

A. Anionic Solution Carbomer (Carbopol 974P B. F. Goodrich) 0.25 gMethyl paraben 0.1 g Sodium hydroxide to pH 7 Flavours, sweeteners,colours q.s. Purified water to 100 ml B. Cationic Solution Chitosanchloride (Seacure CL 211, 2 g Pronova Biopolymer) Methyl paraben 0.1 gFlavours, Sweeteners, colours q.s. Purified water to 100 ml

Solution A

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Create a vortex in the solution and disperse the carbomer. Stir untilwell dispersed.

3. Add sodium hydroxide (as a 20% aqueous solution) and stir slowlyuntil homogenous.

4. Check pH is between 6.5 and 7.5 and adjust volume.

Solution B

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Create a vortex in the solution and disperse the chitosan chloride.Stir until dissolved.

When between 0.2 ml and 1 ml of both Solutions A and B are sprayedsimultaneously onto the back of the throat of a sore throat sufferer asoothing protective film is formed.

EXAMPLE 7

As Example 6 but Solution A also contains 0.16 g amylmetacresol and 0.24g dichlorobenzyl alcohol.

EXAMPLE 8

As Example 6 but Solution A also contains 1.6 g calcium carbonate and2.6 g sodium bicarbonate.

When a 5 ml spoonful of Solution A is swallowed, followed after 10 to 30seconds by a 5 ml spoonful of Solution B, a protective film is formed inthe oesophagus which has neutralisation capacity to protect againstgastric reflux.

EXAMPLE 9

A. Anionic Solution Sodium alginate (LFR 5/60, 5 g Pronova Biopolymer)Methyl paraben 0.1 g Flavours, sweeteners, colours q.s. Purified waterto 100 ml B. Cationic Solution Chitosan hydrochloride 1 g (Seacure CL211, Pronova biopolymer) Methyl paraben 0.1 g Flavours, sweeteners,colours q.s. Purified water to 100 ml

Solution A

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Create a vortex in the solution and disperse the sodium alginate.Stir until dissolved.

Solution B

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Create a vortex in the solution and disperse the chitosan chloride.Stir until dissolved.

When 0.2 to 1 ml of each solution are sprayed simultaneously onto theback of the throat a soothing protective film is formed.

EXAMPLE 10

As Example 1 but Solution A also contains 216 mg of buprenorphinehydrochloride.

When 0.1 ml of Solution A, followed immediately by 0.1 ml of Solution B,are sprayed onto the underside of the tongue a film is formed providingsystemic (sublingual) delivery of buprenorphine hydrochloride.

EXAMPLE 11

As Example 1 but Solution A also contains 10 g povidone iodine complex.

When 5 ml of Solution A, immediately followed by 5 ml of Solution B, aresprayed onto a skin wound a protective/disinfecting film is formed.

EXAMPLE 12

A. Anionic Solution Amidated low methoxy Pectin 6 g Methyl paraben(preservative) 0.1 g Flavours, sweeteners, colours q.s. Purified waterto 100 ml B. Cationic Solution Chitosan chloride 0.4 g (Seacure CL 211,Pronova Biopolymer) Methyl paraben (preservative) 0.1 g Flavours,sweeteners, colours q.s. Purified water to 100 ml

Solution A

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Create a vortex in the solution and disperse the amidated pectin.Stir until dissolved.

Solution B

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Create a vortex in the solution and disperse the chitosanhydrochloride. Stir until dissolved.

Between 0.2 and 1 ml of each solution may be sprayed simultaneously ontothe back of the throat to form a soothing protective film. This film isof particular benefit to those suffering from a sore throat.

EXAMPLE 13

As Example 12 but the Anionic Solution (A) contains 10% pectin and theCationic Solution (B) contains 2% w/v chitosan hydrochloride.

EXAMPLE 14

As Example 12 but the Cationic Solution (B) also contains 0.66% w/vlignocaine hydrochloride.

When 0.5 ml of Solution B immediately followed by 0.5 ml of Solution Aare sprayed onto the back of the throat a soothing protective film isformed, which also delivers a dose of 3.3 mg of lignocaine hydrochlorideproviding a local anaesthetic effect.

EXAMPLE 15

A. Anionic Solution As Example 12. B. Cationic Solution Chitosanchloride 0.4 g (Seacure CL 211, Pronova biopolymer) Methyl paraben 0.1 gBenzocaine 0.2 g Amylmetacresol 0.16 g Dichlorobenzyl alcohol 0.24 gFlavours, sweeteners, colours q.s. Purified water to 100 ml

Solution B

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Add the benzocaine, amylmetacresol and dichlorobenzyl alcohol. Stiruntil dispersed.

3. Create a vortex in the solution and disperse the chitosan chloride.Stir until dissolved.

Spray 0.5 ml of Solution B onto the throat immediately followed by 0.5ml of Solution A. A soothing protective film having local antibacterialand local anaesthetic properties is formed at the back of the throat.

EXAMPLE 16

A. Anionic Solution Low methoxy amidated pectin 6 g Methyl paraben 0.1 gFlavours, sweeteners, colours q.s. Purified water to 100 ml B. CationicSolution Chitosan hydrochloride 1 g (Seacure CL 211, Pronova biopolymer)Methyl paraben 0.1 g Flavours, sweeteners, colours q.s. Purified waterto 100 ml

Solution A

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Create a vortex in the solution and disperse the pectin. Stir untildissolved.

Solution B

1. Dissolve the methyl paraben, flavours, sweeteners and colours in thewater.

2. Create a vortex in the solution and disperse the chitosan chloride.Stir until dissolved.

When 0.2 to 1 ml of each solution are sprayed simultaneously onto theback of the throat a soothing protective film is formed.

EXAMPLE 17

Chitosan chloride (Seacure CL211, Pronova 2 g Biopolymer a.s.) Sodiumalginate (LFR5/60, Pronova Biopolymer a.s.) 10 g Flavours, sweetenerscolours and preservatives q.s. Propylene glycol to 100 g

The sodium alginate and chitosan chloride powders are dispersed inpropylene glycol. The remaining ingredients are then added and mixeduntil dispersed to form a sprayable liquid formulation. The formulationis filled into a suitable spray pack and between 0.2 and 1.0 ml of thesuspension is sprayed onto the back of the throat to provide a soothingprotective film. This formulation is of particular benefit to sorethroat sufferers.

EXAMPLE 18

A formulation identical to that of Example 17 but including 0.66%lignocaine hydrochloride was prepared. 0.5 ml of a solution of theformulation was sprayed onto the back of the throat to provide asoothing protective film. The film also delivered a dose of 3.3 mg oflignocaine hydrochloride to provide a local anaesthetic effect.

EXAMPLE 19

A formulation identical to the formulation of Example 18 but furtherincluding Benzocaine 0.2 g, Amylometacresol 0.16 g, and Dichlorobenzylalcohol 0.24 g was prepared in the manner described in Example 17. 0.5ml of a solution of the formulation was sprayed onto the back of thethroat to provide a soothing protective film which also delivered a doseof local anaesthetic and an anti-bacterial agent. This formulationprovided a treatment for sore throats.

EXAMPLE 20

The formulation of Example 20 is identical to the formulation of Example19, except that the propylene glycol base was replaced by a medium chaintriglyceride oil (Miglyol, Huls Chemicals).

EXAMPLE 21

The formulation of Example 21 is identical with the formulation ofExample l9, except that the propylene glycol base is replaced byTranscutol (a glyceride-based liquid from Gattefosse).

EXAMPLE 22

Carbomer (Carbopol 974P, B. F. 0.25 g Goodrich) Chitosan chloride(Seacure CL211, 2 g Pronova Biopolymer a.s.) Flavours, sweetenerscolours and q.s. preservatives Medium chain triglyceride oil 100 g(Miglyol 812)

The chitosan chloride powders are dispersed in propylene glycol. Theremaining ingredients are then added and mixed until dispersed. Theresulting dispersion is filled into a suitable spray pack. Between 0.2and 1.0 ml of the suspension was sprayed onto the back of the throat toprovide a soothing protective film. The film soothes sore throats.Further examples of non-aqueous liquid-bases which may be used alone orin combination are: Polyethylene glycol 200 to 400, evening primroseoil, neem tree oil, vegetable oils such as arachis oil and tea tree oil.

Example 23

Chitosan chloride (Seacure CL211, 8 mg Pronova Biopolymer a.s.) Sodiumalginate (LFR5/60, Pronova 17 mg Biopolymer a.s.) Triclosan 25 mgLecithin 5 mg Colloidal silicon dioxide 4.5 mg Medium chain triglycerideoil 500 mg

The ingredients were mixed together and filled into a hard gelatincapsule shell using conventional liquid filling equipment for liquidfilling hard gelatin capsules. The capsule was dispersed in 0.1Mhydrochloric acid at 37° C. in order to simulate gastric conditions. Thecapsule ruptures and the contents gel to form a matrix due to theinteraction of the polymers. The bulk of the gelled matrix remainsintact for over 12 hours, slowly releasing the triclosan by diffusionand erosion processes. On ingestion, the capsule provided slow releaseof the drug into the stomach to provide a continued concentration oftriclosan in the stomach for several hours; this provided an effectivetreatment of H. Pylori infections.

EXAMPLE 24

Chitosan chloride (Seacure CL211, 8 mg Pronova Biopolymer a.s.) Sodiumalginate (LFR5/60, 17 mg Pronova Biopolymer a.s.) PseudoephedrineHydrochloride 120 mg Lecithin 5 mg Colloidal silicon dioxide 4.5 mgMedium chain triglyceride oil 500 mg

The ingredients were mixed together and filled into a hard gelatincapsule shell using conventional liquid filling equipment for liquidfilling hard gelatin capsules. The resulting capsule provides a slowrelease of water soluble drug over the period of 12 hours, with theadvantage of reducing the required dosing frequency as compared withstandard dosage forms such as tablets.

EXAMPLE 25

Chitosan chloride (Seacure CL211, 10 mg Pronova Biopolymer a.s.) Sodiumalginate (LFR5/60, Pronova 30 mg Biopolymer a.s.) Triclosan 25 mgGelucire 53/60 (Gattefosse) 300 mg

The Gelucire 53/60 was melted and the remaining ingredients were addedto the melt and dispersed. The resulting mixture was filled into hardgelatin capsules and allowed to set. On ingestion, the capsule slowlyreleased the contents from the waxy matrix which had gelled at thesurface due to the interaction of the polymers.

EXAMPLE 26

Chitosan chloride (Seacure CL211, 28.0% Pronova Biopolymer a.s.) Sodiumalginate (LFR5/60, 71.0% Pronova Biopolymer a.s.) Polyvinyl pyrrolidone(Povidone  1.0% 30 (Kollidon 30 BASF)) Flavours, sweeteners and colourq.s.

The Povidone was dissolved in ethanol to form a 2% solution suitable forgranulating. The chitosan and the sodium alginate were mixed in dry formand a suitable amount of the granulating solution was added to form awet mass. The wet mass was pushed through a 500 μm screen and thescreened wet mass was dried at 25° C. overnight to remove the ethanol.The resulting dry granules were passed through a 150 μm screen and fineparticles were sieved off through a 53 μm screen. The resulting granuleswere collected and filled into a size 2 capsule shell withoutcompacting. The capsules were put into a Spinhaler (TM of Fisons) deviceand the device was primed to rupture the capsule so as to provide a drypowder for inhalation. The inhaled powder coated the inside of the mouthand throat and provided a soothing coating which protected againstfurther mechanical irritation in the case of sore throats, sore mouthsand ulcers.

EXAMPLE 27

The formulation of Example 27 is identical with the formulation ofExample 26, except that the formulation of Example 27 also includedbenzocaine hydrochloride. The benzocaine hydrochloride was added to thegranules in such an amount that each 40 mg of granules contained lOmg ofbenzocaine hydrochloride. The formulation was coated inside the mouth inthe same manner as in Example 10 and provided local anaesthetic painrelief in addition to the soothing and protecting effects describedabove.

EXAMPLE 28

A bilayer tablet was formed using the following ingredients:

Layer one: Sodium alginate (LFR 5/60, 125 mg Pronova Biopolymer a.s.)Polyvinyl pyrrolidone 25 mg (Povidone 30 (Kollidon 30 BASF)) Mannitol350 mg Flavours and sweeteners q.s. Magnesium stearate 15 mg Layer two:Chitosan chloride (Seacure CL211, 50 mg Pronova Biopolymer a.s.)Polyvinyl pyrrolidone (Povidone 25 mg 30 (Kollidon 30 BASF)) Mannitol425 mg Flavours and sweeteners q.s. Magnesium stearate 15 mg

Each layer was separately prepared in the same manner. For each layer,all the ingredients except the flavour and the magnesium stearate weremixed in a high-speed mixer granulator. The mixture was granulated byadding isopropanol (200 mls per Kg) and the granulated mixture wassubsequently dried at 50° C. in a fluid bed dryer. The dried granuleswere sieved after which the flavour and magnesium stearate were addedand mixed with the granules so as to give the final tablet mix for eachlayer. The two separate layers were then pressed into tablets on abilayer press. When the tablets were sucked, they slowly releasedpolymer from each side which then interacted with each other to form afilm on the surface of the mouth and throat. The resulting film providedrelief for sufferers of dry mouth and sore throats.

EXAMPLE 29

The formulation of Example 29 is identical to the formulation of Example28, except that the formulation included calcium carbonate (100 mg) andmagnesium trisilicate (100 mg) in each layer. On sucking the bilayertablets, the polymers interacted to form a neutralising coating in theoesophagus which protected against acid reflux.

EXAMPLE 30

Layer one: Carbomer (Carbopol 974P, B F Goodrich) 80 mg Sodiumbicarbonate 15 mg Polyvinyl pyrrolidone (Providone 25 mg 30 (Kollidon 30BASF)) Mannitol 350 mg Flavours and sweeteners q.s. Magnesium stearate15 mg Layer two: Chitosan chloride (Seacure CL211, 50 mg pronovaBiopolymer a.s.) Polyvinyl pyrrolidone (Providone 25 mg 30 (Kollidon 30BASF) Mannitol 425 mg Flavours and sweeteners q.s. Magnesium stearate 15mg Lignocaine hydrochloride 3.3 mg

The bilayer tablet was prepared in the same manner as for Example 28.When sucked, the bilayer tablet provided a local anaesthetic to themouth and throat which relieved the pain of ulcers and sore throats. Thepolymers reacted to give a soothing protective film which additionallyheld the local anaesthetic in place so as to give a longer duration ofaction.

Further active ingredients which are suitable for incorporation in asustained release formulation such as those exemplified above include:

Pseudoephedrine hydrochloride

Dextromethorphan hydrobromide

Diclofenac sodium

Ketoprofen

Theophylline hydrobromide

Sodium cromoglycate

Ketoconazole

Isosorbide dinitrate

What is claimed is:
 1. A non-aqueous liquid formulation for forming apharmaceutically acceptable polymeric material in situ at a bodysurface, the formulation comprising: (i) a water soluble salt of alginicacid or a water-soluble or water-dispersible salt of a polyacrylic acid(component (a)); (ii) a cationic polymer (component (b)); and (iii) apharmaceutically acceptable inert filler or carrier selected from thegroup consisting of glycols, medium chain triglycerides, glycerides,evening primrose oil, neem tree oil and vegetable oils, whereincomponent (a) is capable of reacting with component (b) to form thepharmaceutically acceptable polymeric material in situ at a body surfacefollowing application to or ingestion by a mammal.
 2. A formulationaccording to claim 1 wherein the polymeric material is a bioadhesivecoating, a film or gel.
 3. A formulation according to claim 1 whereinthe concentration of component (a) in the polymeric material is from 0.1to 75% weight per volume (w/v).
 4. A formulation according to claim 3wherein the concentration of component (a) in the polymeric material isfrom 0.5 to 25% w/v.
 5. A formulation according to claim 1 whereincomponent (b) is selected from the group consisting of water-solublechitosan salts, polylysine, chondroitin salts, diethylaminoethyldextran, and keratin.
 6. A formulation according to claim 5 wherein theconcentration of component (b) in the polymeric material is from 0.1 to75% weight per volume (w/v).
 7. A formulation according to claim 6wherein the concentration of component (b) in the polymeric material isfrom 0.5 to 25% w/v.
 8. A formulation according to claim 2 in which theweight ratio of component (a) to component (b) ranges from 1:10 to 10:1.9. A formulation, according to claim 8 in which the weight ratio rangesfrom 1:2 to 2:1.
 10. A formulation according to claim 2 in whichcomponent (a) is a water-soluble alginate salt and component (b) is awater-soluble chitosan salt, dimethylaminoethyl dextran or chondroitinsulfate.
 11. A formulation according to claim 10 in which component (b)is a water-soluble chitosan salt.
 12. A formulation according to claim 2in which component (a) is a water-soluble or water-dispersible salt of apolyacrylic acid and component (b) is a water-soluble chitosan salt,dimethylaminoethyl dextran or chondroitin sulfate.
 13. A formulationaccording to claim 12 in which component (b) is a water-soluble chitosansalt.
 14. A formulation according to claim 1 wherein the polymericmaterial further comprises one or more active agents selected from thegroup consisting of: acetaminophen, ibuprofen, naproxen, diclofenac,ketoprofen, choline salicylate, benzydamine, buprenorphine,hydrocortisone, betamethasone, pseudoephedrine, phenylephrine,oxymetazoline, xylometazoline, zinc gluconate, zinc acetate,dextromethorphan, codeine, pholcodine, guaiphenesin, N-acetylcysteine,bromhexine; triclosan, chloroxylenol, cetylpyridinium chloride,benzalkonium chloride, amylmetacresol, hexylresorcinols, dichlorobenzylalcohol, benzyl alcohol, dequalinium chloride, silver sulphadiazine,glyceryl trinitrate, lignocaine, benzocaine, carbenoxolone, sucralfate,bismuth subsalicylate, calcium carbonate, sodium bicarbonate, magnesiumtrisilicate, magaldrate, cimetidine, ranitidine, nizatidine, famotidine,omeprazole, pantoprazole, loratidine, terfenadine, diphenhydramine,chlorphenhydramine, triprolidine, acrivastine, prochlorperazine,sumatriptan, diphenoxylate, loperamide, sennosides, clotrimazole,fusafungine, tyrothricin, dithranol, calcipotriol, and pharmaceuticallyacceptable mixtures thereof.
 15. A formulation according to claim 14 inwhich the active agent is contained in component (a).